The aims for the continuation of this project are centered on the most significant findings of my previous study: That cannabidiol (CBD) treatment produces both inactivation and induction of specific mouse hepatic cytochrome P-450(P-450) isozymes, resulting in altered capacity for metabolism of CBD and other cannabinoids. These findings suggest important clinical pharmacological consequences, since an alteration P-450 will affect the metabolism of most drugs concurrently ingested with CBD (a major constituent of marijuana), resulting in either decreased or increased elimination of those drugs. Altered metabolism could also affect the pharmacological response to tetrahydrocannabinol (THC), whose actions are believed to be mediated by THC metabolites. This proposal is designed to identify the chemical determinants of CBD involved in the inactivation process, and will aim to elucidate the mechanism of CBD- mediated P-450 induction. Rat and mouse hepatic P-450 appear to be differentially inhibited by CBD, and since P-450 induction is often observed after P-450 inhibition, possible differences in the mechanisms of CBD-mediated inhibition and induction in the two species will be examined. Biochemical changes and alterations in the genetic regulation of P-450 isozymes affected by CBD will be assessed. Because changes in P-450 isozymes are expected to affect THC metabolism, THC metabolites found to be formed in altered quantities after CBD treatments will be chemically synthesized and tested for pharmacological effects. In addition, the effect of CBD treatment on the metabolism of THC and other compounds by brain P-450 will also be determined. Thus, the overall goals of this study are to determine the mechanisms involved in CBD-mediated P-450 inactivation and induction, as well as to assess the consequences of such P-450 alterations on THC metabolism and action.